1. Field of the Invention
This invention relates to a novel tetrapeptide derivative having an antitumor activity, and relates more particularly to a tetrapeptide derivative represented by the following formula or a salt thereof: ##STR5## wherein, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are the same or different and each represent a hydrogen atom, a lower alkyl group or an aralkyl group;
Q represents ##STR6## or a group of --A.sub.2 --R.sub.7, wherein, PA1 A.sub.1 represents a direct bond or ##STR7## Y represents a hydrogen atom or --COR.sub.6, R.sub.5 represents a hydrogen atom, a lower alkyl group or an aralkyl group, PA1 R.sub.6 represents a hydroxyl group, a lower alkoxy group, an aralkyloxy group or ##STR8## wherein, R.sub.8 and R.sub.9 are the same or different and each represent a hydrogen atom, a lower alkyl group, a phenyl group or a 4- to 7-membered heterocyclic group containing one or two hetero atoms selected from S, O and N, or alternatively PA1 R.sub.8 and R.sub.9 may combine together with the nitrogen atom to which they are bonded to form a 4- to 7-membered heterocyclic ring optionally further containing one hetero atom selected from S, O and N, PA1 A.sub.2 represents a direct bond or a lower alkylene group, and PA1 R.sub.7 represents a cycloalkyl group, an aryl group or an indolyl group, provided that the case is excluded where both R.sub.1 and R.sub.2 represent isopropyl groups, R.sub.3 represents a sec-butyl group, R.sub.4 represents a methyl group, and Q represents an .alpha.-(2-thiazolyl)phenethyl group. PA1 (1) Amino acid-substituted compounds of dolastatin 10 and synthesis thereof PA1 (2) Carboxyl derivatives of the thiazole ring and synthesis thereof PA1 (3) Tetrapeptide derivatives wherein the thiazole ring is eliminatd and synthesis thereof PA1 Q represents ##STR11## wherein R.sub.5 has the same meaning as defined above, and particularly preferable among them are compounds wherein four groups among R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 represent the same groups as in dolastatin 10 (i.e., compounds wherein both R.sub.1 and R.sub.2 are isopropyl groups, R.sub.3 is a sec-butyl group, R.sub.4 is a methyl group and R.sub.5 is a benzyl group), and only the residual one group represents a group different from that in dolastatin 10.
2. Description of Related Art
Peptides having a cytostatic activity and/or an antineoplasm activity have been isolated from marine molluscs, sea hare Dolabella auricularia and these peptides are called dolastatins 1 to 15. Among them, dolastatin 10 is a pentapeptide extracted from Dolabella auricularia from the Indian Ocean in 1987 by G. R. Pettit, et al. and having the following structural formula, and is said to be the strongest cytostatic substance presently known (see G. R. Pettit, et al., J. Am. Chem. Soc., 109, 6883 (1987) and Japanese Laid-Open Patent Publication No. 167278/1992). ##STR9##
Further, recently, publication was made on the total synthesis of dolastatin 10 itself (see, U.S. Pat. No. 4,978,744), but its derivatives have not so far been known at all.
The present inventors have intensely studied derivatives of dolastatin 10, and as a result they found that certain dolastatin analogs represented by the above formula (I) have a higher cytostatic activity than dolastatin 10. They further found that many of these compounds have a larger therapeutic ratio (maximum effective dose/dose at 30% prolongation of life) and a lower toxicity than dolastatin 10, and are thus excellent as an antitumor agent.
Namely, they found not only that amino acid analogs of dolastatin 10 exhibit a higher activity than the native dolastatin 10, but that the activity is, unexpectedly, extremely increased by introducing a carboxyl derivative into the thiazole ring. Further, they found, thoroughly astoundingly, that derivatives wherein the thiazole ring is eliminated show extremely higher activity than dolastatin 10.